2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647575摘要：多發性骨髓瘤是骨髓中漿細胞癌化而來的腫瘤。至今，其形成的原因仍不清楚，也還無法治癒。B lymphocyte induced maturation protein-1 (Blimp-1)，一個轉錄因子，負責調控B 淋巴細胞分化至漿細胞，其持續表現和漿細胞存活息息相關。最近，Blimp-1 被發現和淋巴癌形成有關。加上骨髓瘤細胞株所發現的Blimp-1 變異蛋白(Blimp-1β)，由於失去正向調控區，而導致其抑癌功能下降。這個發現支持Blimp-1 在淋巴惡性病的發生機轉上扮演重要的角色。此外，持續活化的nuclear factor-κB (NF-κB)也被認為是淋巴惡性病(包括骨髓瘤)的致癌機制之一。A20 基因及其蛋白，是此路徑的負向調控因子。最近在一些淋巴癌的檢體中，發現A20 常常被剔除，或是被去活化，造成其失去負向調控NF-κB 的能力。有趣的是，上述Blimp-1 和A20，皆在染色體6q，分別在6q21-22.1 和 6q23.3-24.1。我們研究顯示骨髓瘤染色體6q 發生變化的比例為16%。因此我們計畫用螢光原位雜交法(FISH)，針對這兩個基因區域(6q21-24)，分析其在骨髓瘤變化的比例。研究Blimp-1 及Blimp-1β 在骨髓瘤病人的表現，以及A20 基因去活化的比例。加上基因轉殖骨髓瘤細胞株，用以調控Blimp-1 和A20 基因的表現，及動物實驗合併藥物治療，茲以和病人的臨床特徵，治療預後做比對。我們相信此結果能為骨髓瘤形成機轉提供一個新的見解，而針對這兩個基因及所調控的分化和NF-κB 路徑，也可以開發出新的治療策略。<br> Abstract: Multiple myeloma (MM) is a clonal plasma cell (PC) neoplasm characterized byproliferation of neoplastic PC in bone marrow (BM). The pathogenesis of MM is stillnot clear, and although there has been some advance in the treatment, which is stillincurable yet. To explore the pathogenesis and seeking for potential novel therapeutictargets for MM are warranted. Recently, B lymphocyte-induced maturation protein(Blimp-1), a transcriptional factor (repressor) to control the terminal differentiation ofmature B cells to plasma cells, was found to be important in the pathogenesis oflymphoma by which mutational inactivation of Blimp-1 has been identified in a subsetof diffuse large B-cell lymphomas of the activated B-cell type. In addition, an importantrole for Blimp-1 in maintaining the normal PC is emerging and high expression ofBlimp-1β, a splicing variant of Blimp-1 without positive regulatory (PR) domain, as aresult of loss of tumor suppressor function, was found in MM cell lines. However, thesignification of expression of Blimp-1 or Blimp-1β in MM patients is not clear yet. Theconstitutive activation of nuclear factor-κB (NF-κB) has been implicated intumorigenesis of lymphoid malignancies, including MM. More recently, a newlydescribed TNFAIP3/A20 gene [tumor necrosis factor, alpha-induced protein 3(TNFAIP3) gene (also known as A20)], a negative regulator of NF-κB pathways, wasfound frequently deleted or inactivated in several subsets of non-Hodgkin’s lymphomathrough several different mechanisms, like promoter methylation or gene mutation.However, whether the inactivation of the TNFAIP3/A20 gene is important for MMpatients is also not clear. Intriguingly, both genes, Blimp-1 and TNFAIP3/A20 arelocated in chromosome 6q, involving bands 6q21-6q22.1 and 6q23.3-q24.1, respectively.According to our previous study, aberrations of chromosome 6q was found in about16% of our patients with newly diagnosed MM, therefore, we would like to evaluate theexpression of Blimp-1 and the variant Blimp-1β protein in our MM patients, as well asthe frequency of inactivation of TNFAIP3/A20 gene in the same cohort of patients.Further to correlate the clinical features and outcome to those patients with Blimp-1and/or Blimp-1β expression and/or inactivation of TNFAIP3/A20 gene on their tumorsamples. These results may provide a novel insight into molecular mechanisms leadingto pathogenesis of MM and that specific targeting of Blimp-1 and/or the TNFAIP3/A20gene associated NF-κB pathways may be advantageous for treatment.A20/TNFAIP3Blimp-1NF-κB多發性骨髓瘤預後治療TNFAIP3/A20Blimp-1NF-κBMultiple myelomaPrognosisTreatment